rs12771333

Variant names:

• chr10-19387632-G-A
• rs12771333
• NM_001142308.3:c.4546G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001142308.3(MALRD1):​c.4546G>A​(p.Glu1516Lys) variant causes a missense change. The variant allele was found at a frequency of 0.136 in 1,550,002 control chromosomes in the GnomAD database, including 15,229 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1088 hom., cov: 31)
  • Exomes 𝑓: 0.14 (14141 hom.)
• Consequence: MALRD1 NM_001142308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.20
• Publications: 5 publications found

Genes affected

MALRD1 (HGNC:24331): (MAM and LDL receptor class A domain containing 1) This gene encodes a conserved protein that features multiple MAM (meprin-A5-protein tyrosine phosphatase mu) and LDLR A2 (low density lipoprotein receptor A2) domains. Expression of this gene is enriched in the small intestine and is upregulated during differentiation of a human cell line that exhibits properties of intestinal epithelial cells. The encoded protein has been shown to modulate production of FGF19 in a human intestinal cell line and may regulate bile acid metabolism in the liver. A synergistic interaction between an allele of this gene and the APOE E4 allele is associated with an elevated risk of Alzheimer's disease in human patients. [provided by RefSeq, Jul 2017]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029085875).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142308.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALRD1	NM_001142308.3	MANE Select	c.4546G>A	p.Glu1516Lys	missense	Exon 27 of 40	NP_001135780.2	Q5VYJ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MALRD1	ENST00000454679.7	TSL:1 MANE Select	c.4546G>A	p.Glu1516Lys	missense	Exon 27 of 40	ENSP00000412763.3	Q5VYJ5
	MALRD1	ENST00000377266.7	TSL:5	c.2473G>A	p.Glu825Lys	missense	Exon 13 of 25	ENSP00000366477.3	U5GXS0

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17510 AN: 151944 Hom.: 1090 Cov.: 31

Gnomad AFR AF: 0.0762

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0964

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.0951

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.122 AC: 18251 AN: 149280 AF XY: 0.127

Gnomad AFR exome AF: 0.0778

Gnomad AMR exome AF: 0.0649

Gnomad ASJ exome AF: 0.0956

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.0906

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.139 AC: 193684 AN: 1397940 Hom.: 14141 Cov.: 32 AF XY: 0.140 AC XY: 96337 AN XY: 689498

African (AFR) AF: 0.0741 AC: 2340 AN: 31588

American (AMR) AF: 0.0681 AC: 2430 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0931 AC: 2345 AN: 25176

East Asian (EAS) AF: 0.111 AC: 3963 AN: 35730

South Asian (SAS) AF: 0.168 AC: 13338 AN: 79218

European-Finnish (FIN) AF: 0.0981 AC: 4726 AN: 48172

Middle Eastern (MID) AF: 0.103 AC: 587 AN: 5700

European-Non Finnish (NFE) AF: 0.145 AC: 156325 AN: 1078662

Other (OTH) AF: 0.132 AC: 7630 AN: 57990

GnomAD4 genome AF: 0.115 AC: 17513 AN: 152062 Hom.: 1088 Cov.: 31 AF XY: 0.113 AC XY: 8431 AN XY: 74326

African (AFR) AF: 0.0762 AC: 3164 AN: 41498

American (AMR) AF: 0.0963 AC: 1470 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 331 AN: 3470

East Asian (EAS) AF: 0.143 AC: 735 AN: 5152

South Asian (SAS) AF: 0.168 AC: 809 AN: 4816

European-Finnish (FIN) AF: 0.0951 AC: 1006 AN: 10582

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9593 AN: 67962

Other (OTH) AF: 0.117 AC: 247 AN: 2112

Alfa AF: 0.127 Hom.: 1555

Bravo AF: 0.112

TwinsUK AF: 0.143 AC: 531

ALSPAC AF: 0.146 AC: 562

ExAC AF: 0.122 AC: 2478

Asia WGS AF: 0.153 AC: 531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.022
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.92	T
PhyloP100		4.2
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Benign	0.61	T
Sift4G	Benign	0.067	T
Vest4		0.077
ClinPred		0.014	T
GERP RS		3.1
Varity_R		0.070
gMVP		0.43
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12771333; hg19: chr10-19676561; COSMIC: COSV65989015;